ClinVar Genomic variation as it relates to human health
NM_000049.4(ASPA):c.368G>A (p.Gly123Glu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000049.4(ASPA):c.368G>A (p.Gly123Glu)
Variation ID: 381631 Accession: VCV000381631.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.2 17: 3481734 (GRCh38) [ NCBI UCSC ] 17: 3385028 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 8, 2017 Feb 14, 2024 Oct 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000049.4:c.368G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000040.1:p.Gly123Glu missense NM_001128085.1:c.368G>A NP_001121557.1:p.Gly123Glu missense NM_001321336.2:c.-73-12336C>T intron variant NM_001321337.2:c.-73-12336C>T intron variant NC_000017.11:g.3481734G>A NC_000017.10:g.3385028G>A NG_008399.2:g.13089G>A NG_008399.3:g.12626G>A - Protein change
- G123E
- Other names
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- Canonical SPDI
- NC_000017.11:3481733:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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ASPA | - | - |
GRCh38 GRCh37 |
13 | 475 | |
SPATA22 | - | - |
GRCh38 GRCh37 |
21 | 581 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 17, 2018 | RCV000432912.12 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Oct 19, 2023 | RCV001276652.18 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Sep 23, 2016)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000521113.4
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
The G123E variant in the ASPA gene has been previously reported in two unrelated non-Ashkenazi Jewish individuals diagnosed with CD who harbored G123E and the … (more)
The G123E variant in the ASPA gene has been previously reported in two unrelated non-Ashkenazi Jewish individuals diagnosed with CD who harbored G123E and the A305E common pathogenic variant (Kaul et al., 1996; Zeng et al., 2002). Functional studies of mutant cDNA in COS1 cells showed the G123E variant exhibited 26% of enzyme activity as compared to wild-type (Kaul et al., 1996). The G123E variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G123E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The G123E variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. (less)
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Likely pathogenic
(Jul 17, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002064496.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the ASPA gene demonstrated a sequence change, c.368G>A, in exon 2 that results in an amino acid change, p.Gly123Glu. The p.Gly123Glu … (more)
DNA sequence analysis of the ASPA gene demonstrated a sequence change, c.368G>A, in exon 2 that results in an amino acid change, p.Gly123Glu. The p.Gly123Glu change affects a highly conserved amino acid residue located in a domain of the ASPA protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Gly123Glu substitution. This particular amino acid change has been described in the literature in patients with Canavan disease (PMIDs: 8659549, 12638939). In vitro functional assays demonstrated decreased enzymatic activity for this variant (PMID: 8659549). (less)
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Likely pathogenic
(Aug 18, 2023)
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criteria provided, single submitter
Method: clinical testing
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Spongy degeneration of central nervous system
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004201705.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Oct 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Spongy degeneration of central nervous system
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV004238475.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Aug 16, 2022)
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criteria provided, single submitter
Method: clinical testing
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Spongy degeneration of central nervous system
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001575010.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
ClinVar contains an entry for this variant (Variation ID: 381631). This missense change has been observed in individual(s) with Canavan disease (PMID: 8659549, 12638939). This … (more)
ClinVar contains an entry for this variant (Variation ID: 381631). This missense change has been observed in individual(s) with Canavan disease (PMID: 8659549, 12638939). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 123 of the ASPA protein (p.Gly123Glu). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ASPA protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ASPA function (PMID: 8659549). (less)
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Likely pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Canavan disease
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001463139.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Identification and characterization of novel mutations of the aspartoacylase gene in non-Jewish patients with Canavan disease. | Zeng BJ | Journal of inherited metabolic disease | 2002 | PMID: 12638939 |
Identification and expression of eight novel mutations among non-Jewish patients with Canavan disease. | Kaul R | American journal of human genetics | 1996 | PMID: 8659549 |
Text-mined citations for rs1057521115 ...
HelpRecord last updated May 01, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.